KR100386337B1 - 진핵세포에서부위-특이적돌연변이를위한화합물과그방법 - Google Patents

진핵세포에서부위-특이적돌연변이를위한화합물과그방법 Download PDF

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KR100386337B1
KR100386337B1 KR1019960703040A KR19960703040A KR100386337B1 KR 100386337 B1 KR100386337 B1 KR 100386337B1 KR 1019960703040 A KR1019960703040 A KR 1019960703040A KR 19960703040 A KR19960703040 A KR 19960703040A KR 100386337 B1 KR100386337 B1 KR 100386337B1
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Abstract

본 발명은 제 1 가닥에는 리보뉴클레오티드와 데옥시리보뉴클레오티드를 가지고 제 2 가닥에는 데옥시리보뉴클레오티드를 가지는 폴리뉴클레오티드에 관계한다. 이때 가닥들은 왓슨-크릭 염기쌍이고 이는 올리고뉴클레오티드에 의해 연결되어 폴리뉴클레오티드는 하나의 3' 와 하나의 5' 단부를 가진다. 이들 단부는 폴리뉴클레오티드가 하나의 연속적인 원형 고분자가 되도록 연결될 수 있다. 폴리뉴클레오티드는 표적유전자에 특이적 돌연변이를 유도하기 위해 사용될 수 있다.

Description

진핵세포에서 부위-특이적 돌연변이를 위한 화합물과 그 방법
제 1 도는 2개 키메라 벡터의 대표적인 구조도이다.
다음은 특별히 라벨링된 것이다: 1, 제 1 가닥;
2-제 2 가닥; 3, 이형부분; 4-동형부분; 5-링커;
6, 연결부위.
제 1A 도는 R-D-R형에서 연결된 키메라 벡터이다.
제 1B 도는 하나의 3' 와 5' 단부를 가지는 R-D-R 형에서 머리핀 키메라 벡터이다.
본 출원은 1993년 12월 9일자 연속출원번호 08/164,303 이다.
1. 발명의 분야
본 발명은 분자유전학분야에 관계한다. 특히, 살아있는 조직배양된 진핵세포로 특정 유전학적 변이를 유도하기 위한 핵산 화합물과 이들의 이용방법에 관계한다. 또한 특별하게는 왓슨-크리크 쌍 2중나선 핵산에 관계하고 이때 이중나선의 한가닥의 일부는 뉴클레오티드를 포함하는 2'-O 또는 2'-OMe 리보스를 포함하고 나머지는 데옥시리보스 뉴클레오티드를 포함한다.
2. 발명의 배경
2.1. 화학적 그리고/또는 하이브리드 이중나선 핵산
본 발명의 분야는 핵산에 관계한다. 핵산은 이형고분자 예로써 비-동일성 유닛의 고분자이고 이는 방향성을 가지는 포스포디에스테르 결합 또는 이들의 유도체에 의해 고분자내로 연결된다. 이중사슬핵산은 핵산이고 이중나선의 제 1 가닥의 각 염기는 과정에 따라 이중사슬의 제 2 가닥의 염기에 상응하게 되고 이때 우라실 또는 티민이 상응하게 되고 시토신과 구아닌이 상응하게 된다. 이들의 상보성을 가지는 반-평행 이중나선 가닥을 왓슨-크릭 쌍이라 한다. 이중사슬핵산은 2개 주요형이 될 수 있는데 리보핵산과 데옥시리보핵산이 된다. 각 리보뉴클레오티드는 등가의 데옥시리오 뉴클레오티드를 가지는데 예로 아데노신과 데옥시아데노신, 시티딘과 데옥시시티딘, 구아노신과 데옥시구아노신, 우리딘과 티민딘이다. 이분야에서 사용할때 핵산, 리보뉴클레오티드와 데옥시리보뉴클레오티드는 동일가닥에 있고 이는 혼합형 또는 키메라(이하 "키메라"라 칭함) 핵산이라 한다. 이중사슬핵산에서 데옥시리보뉴클레오티드와 리보뉴클레오티드는 서로 하이브리드-이중나선이라 한다. 2가닥이 이들 염기 모두보다 적은 이중나선 핵산부분을 형성할때 생성분자는 이형이중나선이 된다.
이중사슬핵산의 2가닥은 공유결합은 하지 않으나 서로 왓슨-크릭 염기쌍만에의해 연합된다. 그러나 이중사슬의 2가닥은 하나의 고분자를 형성하기 위해 올리고뉴클레오티드에 의해 연결될 수 있다. 연결되는 올리고뉴클레오티드는 왓슨-크릭 염기쌍이 아니다. 이형이중나선에서 제 1 과 제 2 가닥은 하나의 고분자의 일부가 되고 이는 "머리핀 이중나선" 또는 "줄기와 루프" 구조가 된다. 전자를 이하에서 사용하게 된다.
여기에서 사용할때 키메리즘은 핵산 고분자의 성질이 있고 하이브리디즘은 이중사슬의 성질이 있다. 예로써 mRNA와 이의 주형은 하이브리드 이중사슬을 형성하고 이는 키메라는 아닌데 예로써 키메라 옥타뉴클레오티드 5'd(TTTT)-r(CCCC)3' 와 5'r(GGGG)-d(AAAA)3' 는 서로 왓슨-크릭 이중나선을 형성하나 생성된 이중사슬은 하이브리드-이중나선이 아니다. 하이브리드-이중사슬이 아닌 이중사슬핵산을 이하에서부터 "호모-이중사슬"이라 칭한다. 특별한 언급이 없는한 호모-이중사슬 핵산은 이중사슬을 포함하는 데옥시뉴클레오티드만을 말한다. 마지막으로, 하이브리드-이중사슬 핵산이 없더라도 "하이브리드화"로써 왓슨-크릭 이중사슬을 형성하는 것도 언급한다.
X선 회절과 2차원적 NMR 에 의해 합성된 키메라 핵산을 가지는 키메라 그리고/또는 하이브리드 이중사슬 핵산의 구조와 이들 연구에서 이용하기 위한 하이브리드 이중사슬핵산에 대해 흥미가 있다(See, e.g., Salazar, M., et al., 1994, J.Mol.Biol. 241:440-55 and Egli, M., et al., 1993, Biochemistry 32: 3221-37(two stranded chimeric hybrid duplex of the form r3d7·d10); Ban, C., et al.,1994, J.Mol.Biol. 236:275-85(self complementary chimeric hybrid duplex of the form d5r1d4); chou, S.H., 1991, Biochemistry 30:5248-57(self-complementing and non-self-complementing chimeric hybrid duplexes of the form d4r4d4). 이들 이중사슬핵산의 상보적인 가닥은 서로 공유결합이 아니고 단지 왓슨-크릭 염기쌍에 의해서만 연합되어 있다.
합성된 키메라 핵산을 가지는 과학자들의 제 2 집단은 리보자임의 연구와 이용 예로써 자가-절단 또는 다른 RNAs 를 절단하는 RNA 분자에 흥미가 있다(Perreault, J.P., et al., 1990, Nature 344:565; Taylor, N.R., et al., 1992, Nocleic Acids Research 20:4559-65; Shimaya, T., 1993, Nucleic Acids Research 21:2605). 이들 연구에서 키메라 리보자임은 활성이 있고 RNA 리보자임보다는 핵산절단효소 절단에 더욱 저항성이 있다. 키메라 리보자임은 자체-상보적인 것으로 왓슨-크릭 염기쌍 가닥은 공유 결합되어 있다. 키메라의 연구동안에 합성되는 화합물은 전술한 하이브리드-이중사슬분자와는 다르고 키메라 리보자임에서 구조연구에 사용되기 위해 합성되는 것으로 안정한 하이브리드-이중사슬을 포함하지는 않는다. 따라서, DNA 결합임을 가지는 키메라 리보자임은 이들의 기질에 결합하고 하이브리드 이중사슬을 형성한다(Yang, J.H., et al., 1990, Biochemistry 29:11156-60. See also, Sawata, S., et al., 1993, Nucleic Acids Research 21:5656-60; Hendry, P., et al., 1992, Nucleic Acids Research 20:5737-41 Shimayama, T., 1993, Nucleic Acids Research 21:2605). 리보자임은 RNA 기질의절단을 촉매하고 하이브리드-이중사슬이 풀린다.
2.2. 진핵세포에서 부위-직접적인 유전자변환
분자생물학 분야에 숙지된 자는 빈번하게 새로운 유전자와 같은 새로운 폴리핵산 서열을 표적 진핵세포내로 유입하기만을 원하는 것이 아니라 표적세포에서 정의된, 기존유전자를 유입한다. 표적된 세포는 배양시에 이용될 수 있거나 또는 유전자 전이동물을 만드는데 사용될 수 있다.
다양한 기술이 배양된 진핵세포내로 NDA 를 유입시키기 위해 개발되어 왔다. 이와 같은 기술에는 칼슘 포스페이트 침전과 DEAE-덱스트란 조절되는 엔도사이토시스, 일렉트로포레이션, 리포좀 조정된 융합과 복재 무능력 바이러스와의 형질도입등이 포함된다. 그러나, 이와 같은 기술은 종종 진핵세포내로 기능적 유전자를 유입시킬 수 있고 이와 같은 기술은 특정 기존유전자에 변화(돌연변이)를 완성할 수는 없다. 도입후에 외부 DNA 는 유사재조합에 의해 특정위치에서 보다는 비합법적인 재조합에 의해 세포 게놈에서 무작위 위치로부터 분리할 수 있다.
최근까지 고등 진핵세포 예로써 포유류 또는 조류세포에서 부위-직접적 또는 부위-특이적 변환(돌연변이)를 유도하기 위한 일반적인 만족할만한 과정이 없다. 비록 유사 재조합이 매우 긴(>1kb) 핵산의 유입에 의해 고등 진핵세포에서 유입될 수 있으나 이들 기술은 고등 진핵생물에서 비논리적인 재조합율이 유사재조합의 경우보다 상당히 초과하기 때문에 정교한 선택기술 응용이 요구된다(Thomas, K.R. & Capecchi, M.R., 1987, Cell 52:503. See, also, Valancius, V. & Smithies O., 1991, Mol. Cell. Biol. 11:4389(comparison homologous recombination oflinearized and supercoiled plasmids in eukaryotic cells)).
주요부위-직접적인 돌연변이를 얻기 위한 한가지 방법은 세포내로 직접 한가닥 올리고데옥시뉴클레오티드의 도입이다. 이 기술은 이스트 사카로마이세스 세르비시아에서 성공적으로 이용되어 왔고 이때 유사재조합은 고등 진핵 생물에서보다는 상당히 활동적이다(Moerschell, R.P., et al., 1988, Proc.Natl.Acad.Sci. 85:524-28; Yamamoto, T., et al., 1992, Yeast 8:935-48). 그러나, 단일 가닥 올리고뉴클레오티드에 의해 포유류 또는 조류 세포의 성공적인 형질변환의 보고는 없다.
포유류에서 표적 DNA 의 구조와 유사재조합 사이의 관계는 퓨린과 피리미딘 염기의 변화부분 예로써 [d(TG)30·d(AC)30]가 재조합의 속도를 상당히 증가되는 것으로 나타내는 연구에 의해 추론할 수 있다. 이들 효과는 배양된 포유류 세포에서 비-복제 플라스미드의 연구에 의해 설명될 수 있다(Wahls, W.P., et al., 1990, Mol. Cell. Biol. 10:785-93). 이들 실험에서는 외생 핵산과 세포의 게놈사이에 관계를 나타내는데 까지는 연장되지 않는다.
진핵세포에서 유사재조합을 촉진시키기 위해 박테리아, 대장균에서 유사재조합을 촉진시키는 단백질 RecA 를 이용하기 위한 시도가 있었다. 그러나, 이와 같은 시도는 분명하게 성공적인 것은 아니다. 예로써 W. Bertling E. Sena 의 특허 공고 WO93/22443 과 D.C. Gruenert and K. Kunzelmann 의 공고 94/04032 에서는 낭포성 섬유증에 관계된 배양된 세포주에서 유전자 결함을 수정할 수 있는 것으로 보고한다. 이들 공보에서는 작동방법의 실시예와 관계하여 데이타보다는 원리를 설명하는 주요 실험 데이타에 대해 상술한다. 따라서, 핵에 근접하게 폴리뉴클레오티드/RecA 복합체를 유도시키기 위해, Zarling 과 Gruenert 는 세포가 비록 추가의 성장은 할 수 없으나, 막-침투 가능한 세포를 이용한다. 더우기, RecA-촉진된 유사재조합이 고유세포에서 일어난다고 주장하고 있으나 이들 공보에서는 이 빈도의 양적측정에 대해서는 제공하지 못했다. 따라서, 원핵 recA의 이용은 유사재조합의 자발적 속도보다는 상당히 크게 볼 수 있는 진핵세포에서 유사재조합 속도를 확실하게 나타내주지는 못했다.
3. 발명의 요약
본 발명은 데옥시리보뉴클레오티드와 리보뉴클레오티드를 가지는 소요의 유전자와 유사한 단일 공유결합적으로 연결된 이중사슬 올리고뉴클레오티드에 관계한다. 유전적 변화에 영향을 주기 위해 유사범위내에 하나이상의 비-상응(이하 "이형" 또는 "돌연변이") 염기쌍이 있다. 정상적인, 구성적 세포과정은 표적 게놈 부위내로 삽입될 수 있는 돌연변이 뉴클레오티드가 된다. 본 발명의 이중사슬 올리고뉴클레오티드(이하 "키메라 벡터")는 이형 염기쌍을 유전자 내로 유입시킴으로써 소요의 유전자를 특이적으로 변경시키는데 이용될 수 있다. 이형 염기쌍은 소요의 유전자와는 상이한 염기쌍이 될 수 있거나 또는 소요의 유전자에 있는 것에 추가하여 염기쌍이 될 수 있고(삽입) 또는 이형 염기쌍은 소요의 유전자에서 발견되는 염기쌍이 없을 수도 있다(결실). 본 발명은 부분적으로 벡터에서 하이브리드-이중사슬 핵산의 약 15 내지 50 염기쌍 사이에 부위의 삽입은 소요의 유전자의 변경의 속도를 상당히 증가시키게 된다. 이형 염기쌍의 부분이 1 내지 50 염기쌍 일때, 이형 염기쌍은 본 발명의 벡터내에 호모- 또는 하이브리드-이중사슬일 수 있다. 이형 염기쌍이 길이가 50 염기쌍 이상일때 이들은 호모-이중사슬로 있을 수 있다.
벡터는 진핵세포에 핵산의 유입을 허용하기 위해 공지의 방법으로 표적세포내로 유입될 수 있다. 이론에 한정되지 않고 키메라 벡터는 표적세포의 재조합/수리기작에 의해 연결되거나 유전자 전환 또는 유사재조합에 의해 표적유전자의 변경을 직접관여할 수 있다.
5. 발명의 상세한 설명
5.1. 본 발명의 키메라 벡터의 설명
본 발명은 염기를 가지는 데옥시리보스와 리보스를 가지는 이중사슬 핵산에 관한 것이다. 따라서, 여기에는 DNA 와 RNA 부분을 포함하고 이는 "키메라 벡터"라 한다. 키메라 벡터의 리보뉴클레오티드의 2'-O는 메틸화되어 있다. 임의 포스포디에스테르는 포스포로티오디에스테르 또는 메티포스포노디에스테르에 의해 치환될 수 있다.
본 발명의 키메라 벡터는 하나의 핵산고분자이다. 따라서, 본 발명의 키메라 벡터는 왓슨-크릭 염기쌍이 되어 있지 않은 적어도 하나의 염기와 통상 3 또는 4개 이상의 염기에서 적어도 하나를 포함해야 한다. 이들 쌍을 가지지 않는 부분은 왓슨-크릭 쌍을 가진 염기의 두가닥 사이에 링커로써 작용할 수 있다. 합성된 다른 키메라 뉴클레오티드가 쌍을 가지지 않은 효소활성이 없는 뉴클레오티드 키메라 벡터부위를 가지는 것과는 대조적으로, ATP와 같은 생물학적 에너지원이 없이 화학반응 또는 화학반응하에 촉매할 수 없다.
적절한 구체예에서 링커의 염기는 데옥시리보올리고뉴클레오티드이다. 2개 링커를 가지는 키메라 벡터는 고분자의 3'와 5' 단부가 상보 가닥의 인접한 뉴클레오티드에 왓슨-크릭 쌍을 가지도록 만들어질 수 있다. 그다음 이들은 키메라 벡터가 하나의 연속적인 원형 핵산 고분자를 형성하도록 연결될 수 있다.
실제적으로 키메라 벡터의 모든 남아 있는 염기는 왓슨-크릭 염기쌍이다. 여기에서 사용할때 염기는 왓슨-크릭 염기쌍이고 또는 이중사슬 핵산을 형성하기 위해서 적절한 온도조건하에 염기쌍 또는 이중나선 핵산을 형성할 수 있도록 의미하는 것이 이해될 수 있다. 저염 그리고/또는 상승된 온도조건하에서 왓슨-크릭 염기쌍은 이중사슬 핵산이 용융되거나 변성될 수 있도록 열역학적으로 안정되게 할 수 있는 것으로 이해된다. 짝이 맞지 않은 하나 또는 2개 염기쌍은 본 발명의 작동에 영향을 미치지 못하는 것으로 이해된다.
본 발명의 키메라 벡터는 표적유전자로내 돌연변이를 특이적으로 유입시키기 위한 목적을 가진다. 돌연변이의 유전학적 부위는 표적 부위 서열로써 이하에서는 유사부위로 칭하는 동일서열을 가지는 키메라 벡터의 일부를 선택함으로써 결정될 수 있다. 키메라 벡터의 서열과 표적 유전자 사이에 차이가 나는 부위는 이형부분이라 칭한다. 키메라 벡터는 표적유전자와는 다르나, 벡터의 이부분에서 이형이중사슬은 아니다. 본 발명의 적절한 구체예에서, 사이에 끼워진 이형부분에 인접하여 각 키메라 벡터에 2개 유사부분을 가지고 세개 모든 부위는 하나의 연속이중사슬 핵산에 있다. 본 발명에 따르면 각 유사부분에는 하이브리드-이중사슬핵산의 일부를 포함하고 있다. 각 하이브리드-이중사슬의 일부는 적어도 4개 염기쌍일 수 있고 적절하게는 8개 염기쌍이고 더욱 적절하게는 20 내지 30개 염기쌍이 될 수 있다. 키메라 벡터의 기능은 서로 3' 와 5' 단부의 연결을 허용하기 위해 위치한 하이브리드 이중사슬부위내에 호모-이중사슬의 디뉴클레오티드 염기쌍에 의해 영향을 받지는 않는다. 2개 유사부위의 총길이는 적어도 20개 염기쌍이 되고 적절하게는 40 내지 60개 염기쌍이 될 수 있다.
본 발명에 따르면, 호모-이중사슬 핵산의 부위는 벡터의 하이브리드-이중사슬/유사부위 사이에 배치될 수 있다. 끼워진 호모-이중사슬에는 이형부분을 포함할 수 있다. 이형부분이 50 염기쌍이하, 적절하게는 20 염기쌍 이하인 경우 사이에 끼워진 호모-이중사슬 부분의 존재는 선택적일 수 있다. 이형부위가 20염기쌍이 초과할때 이형부분을 포함하는 끼워진 호모-이중사슬이 적절하다.
5.2. 본 발명의 키메라 벡터의 구성
본 발명의 키메라 벡터는 임의의 방법에 의해 합성될 수 있다. 키메라 벡터는 DNA 의 고형상합성에서 이용되는 기술의 수정에 의해 합성될 수 있다(Reviewed Caruthers, M.H., 1985, Science 230:281-85; Itakura, K., et al., 1984, Ann.Rev.Biochem. 53:523-56. Modifications to permit the synthesis of RNA and of chimeric nucleic acids are disclosed in Scaringe, S.A., et al., 1990, Nucleic Acids Research 18:5433-41; Usman, N., et al., 1992, Nucleic Acids Research 20:6695-99; and Swiderski, P.M., et al., 1994, Anal. Biochem 216:83-88, Which are hereby incorporatea by reference in their entirety). 키메라 핵산의 합성에 관계하는 최근의 진보는 Usman, N. & Cedergren, R., 1992, Trends Bioch. Sci. 17:334-9 에서 볼 수 있다.
2개 하이브리드-이중사슬부분 사이에 끼워진 호모-이중사슬부분을 가지는 키메라 벡터는 반합성기술을 이용하여 만들어질 수 있다. 머리핀 구조를 가지는 2개 합성된 키메라 폴리핵산이 만들어질 수도 있다. 2개 키메라 핵산의 자유 5' 와 3' 단부는 2개 상이한 제한효소 유전자 절단 산물의 겹쳐지는 부분에 상보적인 겹쳐지는 단부로 만들어질 수 있다. 호모-이중사슬부위는 상보적인 제한효소 절단된 단부를 가지도록 제공될 수 있다. 클론된 DNA 단편의 단부에 제한효소 부위의 추가는 기술분야에 숙지의 지식을 가진자에 의해 이해되는 기술에 의해 실행될 수 있는데, 제한효소를 포함하는 링커의 블런트 단부 연결 또는 연장된 프라이머와의 PCR 증폭이 될 수 있으나 이에 한정함이 아니다. 2개 키메라 뉴클레오티드와 호모-이중사슬 부위는 통상적인 효소기술에 의해 연결될 수 있다. 양단부에서 연결된 키메라 올리고뉴클레오티드를 가지는 생성물은 비-변성 조건하에 트리스 보레이트 EDTA 완충액에 6% 폴리아크릴아미드겔에 전기영동에 의해 불안정한 반응된 기질에서부터 분리될 수 있다. 리니어 캡된 분자가 가두어 질 수 있고 이들 조건하에 더욱 서서히 전기영동될 수도 있다.
오로지 자연적으로 발생하는 뉴클레오티드를 포함하는 키메라 벡터가 본 발명에 사용될 수도 있다. 약 20 리보뉴클레오티드의 하이브리드-이중사슬의 부위를 가지는 키메라 벡터가 시험관에서 RNAse H 에 저항성인 것으로 밝혀졌다. 효소분해에 대한 저항성은 2'-O 메틸화된 리보뉴클레오티드로 리보뉴클레오티드를 대체함으로써 얻을 수 있다. 또는 핵산의 포스포디에스테르 결합이 포스포로티오디에스테르에 의해 대체될 수 있다(Shimayama, T. et al., 1993, Nucleic Acids Research 21:2605). 뉴클레오티드를 포함하는 아라비노즈를 또한 이용할 수도 있다. 여기에서 사용할때 핵산은 이들 수정을 가지는 핵산을 포함하는 의도도 있다.
5.3. 본 발명의 키메라 벡터의 사용
본 발명의 키메라 벡터는 표적세포의 게놈내에 특정위치에 돌연변이를 위해 사용될 수 있다. 표적위치의 특정위치는 이의 핵산서열 이하 표적서열이라 정의한다. 본 발명에 따르면, 키메라 벡터가 만들어지고 유사부위는 하이브리드-이중사슬의 일부지역의 존재를 제외하고는 표적서열과 동일하다. 유도된 변화는 서열의 하나이상의 염기에서 변화 또는 하나이상의 염기 추가가 될 수 있다. 표적서열에서 변화는 20 염기 이하의 추가인 경우 본 발명은 하이브리드 이중사슬의 2부분 이상을 이용하여 실행될 수 있다. 표적서열에서 변화가 50 염기 이상의 추가시에 이형부분이 호모-이중사슬 부분내에 포함될 수 있다.
본 발명의 실행은 키메라 벡터가 표적세포의 핵내로 유입되는 것을 요구할 수 있다. 이와 같은 유입을 일으키는 임의의 방법이 사용될 수 있다. 이와 같은 방법은 일렉트로포레이션, DEAE-덱스트란, CaPO4침전, 리포좀 중재된 융합(LIPOFECTIN)과 직접 주입을 포함한다. 일렉트로포레이션은 특별히 적합하다.
본 발명의 한 구체예에서 키메라 벡터는 유전자 전이동물을 만드는데 사용될 수 있다. 키메라 벡터는 Brinster, R.L. et al., 1989, PROC.NATL.ACAD.SCI86:7087; see also U.S.Patent No. 4,873,191 to T.E. Wagner and P.C. Hoppe 에서 상술한 방법에 따라 직접주사에 의해 난자의 전핵내로 유입될 수 있다. 또는 키메라 벡터는 배간세포내로 유입될 수 있고, 키메라 동물은 정상적인 미분화세포와 배관세포의 응집에 의해 생산될 수 있고, 유전자 전이동물은 Capecchi, M.R., 1989, Science. 244: 1288 방법에 따라 키메라 동물의 자손으로써 회수될 수 있다.
일렉트로포레이션을 이용하여 10,000 처리된 세포당 1세포가 표적서열에서 특이적으로 돌연변이될 수 있다(이하 "형질변환된"). 따라서 본 발명의 실행에는 돌연변이안된 세포의 상당수 가운데에서 형질변환된 세포를 선택하기 위한 방법의 이용을 포함한다. 한 구체예에서 세포의 형질변환은 성장장점을 제공한다. 이와 같은 성장장점의 비-제한적 실시예에는 약물-저항성, 성장조절에서 변경 그리고 대사물질을 이용하는 능력에서의 변경을 포함한다. 또다른 구체예에서 선택방법은 네가티브 선택이 될 수 있고 따라서 형질변환된 세포는 선택조건하에 성장할 수 없게 될 수 있고 형질변환안된 세포는 선택적으로 증식하는 세포를 파괴시키는 조건에 노출시킴으로써 제거될 수 있다.
또는 형질변환된 세포는 면역 형광법에 의해 감지될 수 있는 변형된 세포-표면 항원성 표현형을 가질 수 있고 선택은 Fluorescence Activated Cell Sorter 에 의해 실행될 수 있다.
세포내로 키메라 벡터를 유입시키는 방법이 직접주사일때 전핵주사에 의해 유전자 전이동물을 만들때 형질변환속도는 10,000 세포당 1개 이상일 수 있다. 선택의 필요성은 따라서 상당히 감소된다.
키메라 벡터의 일반적인 이용가능한 양은 일렉트로포레이션에 의해 형질전환될 10,000 배양된 세포당 키메라 벡터의 10 내지 1000ng 이 된다.
6. 실시예
6.1. 실시예: 우스틸라고 곰팡이에서 생체내 활성
야생형 우스틸라그는 기능성이 있는 ura-3 유전자를 가지고 이의 생성물은 우라실 생합성 경로의 일부이다. 야생형 우스틸라고는 5'-플루오로틱산(5FOA)-배지에서 생장시켰을때 세포는 경로내로 산의 결합에 의해 죽게된다. ura-3 유전자가 돌연변이된 경우에 ura-3 mRNA가 생산되지 않고 세포는 5FOA 배지에서 생존한다.
본 기술분야에 내생 ura-3 유전자의 서열은 공지되어 있다.
실험의 한 세트에서 서열의 염기 358 이 티미딘에서 아데닌으로 변경되면 돌연변이로 인하여 이상기능 단백질이 된다.
키메라 벡터는 다음과 같이 합성된다. 염기 358 에서 돌연변이 벡터: (358 RNA 벡터)
358 벡터는 머리핀 모양을 선택한다. 밑줄친 염기는 리보핵산잔기를 나타낸다. 굵은 문자는 돌연변이부분(이형부분)을 나타낸다. 이탤릭체 "T"는 쌍을 가지지 않는 염기를 나타낸다.
동일서열을 가지나 리보핵산을 포함하지 않는 벡터는 콘트롤로써 사용하기 위해 만들어질 수 있다. 벡터에서 티미딘은 우라실로 대체된다.
염기 358:(DNA 358 벡터)에서 돌연변이용 벡터
도 또한 머리핀 모양을 채택한다. 다시, 굵은문자는 돌연변이체가 된다.
생체내 형질변환 실험은 U. 마이디스 세포(107)이 50μl 형질변환 완충액에 106세포의 회수로 원형질내로 만들어질 수 있고 공지된 기술에 따라 상이한 양의 키메라 벡터로 전이감염되거나 또는 동질(DNA 단독) 벡터는 37℃ 에서 원형질과 혼합될 수도 있다. 그다음 세포는 선택배지에서 도말하고 살아있는 콜로니수(형질변환체)를 헤아린다. 그결과는 다음표와 같다.
이들 데이타에서 RNA 358 벡터와 세포의 형질감염은 상응하는 DNA 벡터로 형질감염된 것 이상의 속도에서 세포생존이 증가됨을 볼 수 있다.
6.2. 실시예 2: NIH 3T3 세포의 형질변환
NIH 3T3 세포는 양성(제어된) 성장특징을 가지는 사람세포이다. 악성(제어안된) 성장특징은 Gly12가 Thr 로 대체되는 온코겐 H-ras 에서 단일점 돌연변이에 의한 것이다. 따라서 돌연변이 G→T12는 성장특징에서 선택성 변경을 유도한다(Taparowsky, E., et al., 1982, Nature 300:762; Sukumar S., et al., 1983, Nature 306:658).
키메라 벡터는 다음의 서열을 가지는 G→T12돌연변이에 관계하도록 구성된다.
이 서열은 추가의 특징이 있는 통상의 한문자 코드로 나타내고 RNA(밑줄), 쌍이 아닌 염기는 이태리체이고 돌연변이체 염기는 굵은 문자이다. 원형화한후에 키메라 벡터는 2개 트리티미디닐 서열에 의해 2개 실제 상보서열로 나누어지고 뉴클레오티드를 포함하는 모든 리보즈는 2개 가닥중 하나에만 있다.
키메라 벡터의 2개 형은 4개 데옥시리보즈 잔기에 인접한 하이브리드 이중사슬의 하나("R")과 2개("R-D-R")부분을 가지는 2'-OMe 리보즈 염기를 이용하여 합성될 수 있다. R-D-R형은 전술한 SEQ ID:3 이고 R형은 염기 6-9("CGAC")가 데옥시리보뉴클레오티드인 것을 제외하고는 동일하다. 5' 와 3' 단부는 데옥시뉴클레오티드이다. 동일 DNA 리가제 과정의 이용에 의해 합성된후 키메라 벡터는 재조합 DNA에서 통상적으로 이용될 수 있다. 연결후에, 원형화 키메라 벡터는 D600 겔(AT Biochem, Malvern, PA)에서 준비되는 전기영동의 반복에 의해 기질로부터 분리될수 있다.
콘트롤 벡터는 1) 하이브리드-이중사슬(데이타에서 나타냄 "호모-이중사슬")이 부족한 동일서열; 2) 서열
을 가지는 염기쌍이 안된 서열(데이타에서 나타남 "sDNA"); 3) 이형부분이 없고 돌연변이 서열을 가지지 않는 키메라 벡터(데이타에서 나타내지 않음).
실험은 일렉트로포레이션 과정을 이용하여 NIH 3T3 세포(1×106세포)를 형질변환시킴으로써 실행될 수 있다. 일렉트로포레이션 후에 세포는 밀도 4×103세포/cm 에서 도말할 수 있고 이는 14일간 배양시킬 수 있다. 형질변환체는 자색 결정으로 포카이-형성세포를 착새시킴으로써 볼 수 있다. 포지티브 콘트롤로써 Hras 의 T12형을 인코드하는 플라스미드 pT24 를 이용한다. 이와 같은 콘트롤은 형질감염된 NIH 3T3 세포에서 비논리적 재조합 수준을 결정하기 위해 이용될 수 있다. 실험은 5회 반복하고 결과는 하기 표에서 볼 수 있다. 하기 나타낸 결과에서 돌연변이 코돈을 가지지 않는 사용된 키메라 벡터에서 NIH 3T3 세포의 형질변환된점은 나타내지 않았다.
이들 결과에서 포유류 세포를 형질변환시키기 위해 유사 재조합에 의해 키메라 벡터는 특이적 돌연변이를 유도한다. 이실험에서 형질변환속도는 pT24 포지티브 콘트롤 벡터와 전이감염된 것에서 볼 수 있는 것과 같이 비논리적 재조합에 의한 형질변환속도보다도 크다. 따라서, 키메라 벡터의 사용에 의해 포유류 세포에서 유사 재조합 속도는 비논리적 재조합 속도보다 크다.

Claims (17)

  1. 하나의 3' 단부와 하나의 5' 단부를 가지는 키메라 핵산에 있어서, 핵산의 구성은
    a. 핵산을 제 1 가닥과 제 2 가닥으로 분리하도록 배치된 연속하는 쌍을 가지지 않는 염기부분;
    b. 15개 염기쌍 길이의 왓슨-크릭 염기쌍 부분, 이때 제 1 가닥의 염기는 제 2 가닥의 염기에 상응하고;
    c. 제 1 가닥은 2'-O 또는 2'-OMe 리보즈로 구성된 3개의 연속하는 뉴클레오티드 부분으로 구성되고, 이들 뉴클레오티드는 하이브리드-이중사슬로 왓슨-크릭 염기쌍이 되는 것을 특징으로 하는 키메라 핵산.
  2. 제 1 항에 있어서, 제 2 가닥은 2'-O 또는 2'-OMe 리보즈로 구성된 뉴클레오티드를 포함하지 않는 것을 특징으로 하는 키메라 핵산.
  3. 제 2 항에 있어서, 하이브리드-이중사슬은 2'-데옥시리보즈로 구성된 뉴클레오티드에 의해 인접한 2'-리보즈로 구성된 9개의 연속하는 뉴클레오티드로 구성되는 것을 특징으로 하는 키메라 핵산.
  4. 제 2 항에 있어서, 제 1 가닥은 두 부분의 하이브리드-이중사슬을 형성하는 2'-O 또는 2'-OMe 리보즈로 구성된 두 부분의 연속하는 뉴클레오티드로 구성되고, 각 하이브리드-이중사슬 부분은 4개의 염기쌍을 가지고, 호모-이중사슬의 1개 염기쌍의 끼워진 부분은 상기 하이브리드-이중사슬 부분사이에 배치되는 것을 특징으로 하는 키메라 핵산.
  5. 제 2 항에 있어서, 제 1 가닥은 두 부분의 하이브리드-이중사슬을 형성하는 2'-O 또는 2'-OMe 리보즈로 구성된 두 부분의 뉴클레오티드로 구성되고, 각 하이브리드-이중사슬 부분은 8개의 염기쌍을 가지고, 호모-이중사슬의 4개 염기쌍의 끼워진 부분은 상기 하이브리드-이중사슬 부분사이에 배치되는 것을 특징으로 하는 키메라 핵산.
  6. 제 5 항에 있어서, 호모-이중사슬의 끼워진 부분은 2'-데옥시리보스 염기쌍 4 - 50개로 구성되는 것을 특징으로 하는 키메라 핵산.
  7. 제 5 항에 있어서, 호모-이중사슬의 끼워진 부분은 2'-데옥시리보즈 염기쌍 30 내지 1,000개로 구성되는 것을 특징으로 하는 키메라 핵산.
  8. 제 2 항에 있어서, 5' 와 3' 단부는 연결되는 것을 특징으로 하는 키메라 핵산.
  9. 제 5 항에 있어서, 5' 와 3' 단부는 연결되는 것을 특징으로 하는 키메라 핵산.
  10. 제 6 항에 있어서, 5' 와 3' 단부는 연결되는 것을 특징으로 하는 키메라 핵산.
  11. 제 7 항에 있어서, 5' 와 3' 단부는 연결되는 것을 특징으로 하는 키메라 핵산.
  12. 핵을 가지는 세포의 게놈 표적서열에 예정된 돌연변이를 유도하는 방법에 있어서, 상기 방법은
    a. 표적서열과 상동한 2개 부분 및 이들 사이에 배치되고 돌연변이를 인코드하는 이형부분을 가지는 키메라 벡터를 제공하고;
    b. 키메라 벡터와 표적서열이 유전적으로 복합되도록 세포의 핵내에 키메라 벡터를 유지시키는 단계로 구성되고,
    여기서, 세포는 인간의 세포가 아닌 것을 특징으로 하는 방법.
  13. 제 12 항에 있어서, 핵은 난자의 전핵이고 유입은 직접주사에 의한 것을 특징으로 하는 방법.
  14. 제 12 항에 있어서, 핵은 배아 간세포의 핵이며 유입은 직접 주사인 것을 특징으로 하는 방법.
  15. 변형된 특성을 가지는 세포집단을 수득하는 방법에 있어서, 상기 방법은
    a. 표적서열과 상동한 2개 부분 및 이들 사이에 배치되고 돌연변이를 인코드하는 이형부분을 가지는 키메라 벡터를 제공하고;
    b. 세포의 핵내에 키메라 벡터를 유지시키고, 이때 키메라 벡터와 표적서열은 복합되고 세포는 형질전환되고;
    c. 형질전환된 세포를 선택하는 단계로 구성되고,
    여기서, 세포는 인간의 세포가 아닌 것을 특징으로 하는 방법.
  16. 제 15 항에 있어서, 세포는 인간을 제외한 포유류 세포인 것을 특징으로 하는 방법.
  17. 제 15 항에 있어서, 세포는 이스트 또는 곰팡이인 것을 특징으로 하는 방법.
KR1019960703040A 1993-12-09 1994-12-09 진핵세포에서부위-특이적돌연변이를위한화합물과그방법 KR100386337B1 (ko)

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US5756325A (en) 1998-05-26
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DK0733059T3 (da) 2000-10-16
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CN1117866C (zh) 2003-08-13
JP3585238B2 (ja) 2004-11-04
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US5871984A (en) 1999-02-16
AU691550B2 (en) 1998-05-21
CA2178729A1 (en) 1995-06-15
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DE69425903D1 (de) 2000-10-19
CN1215755A (zh) 1999-05-05
ATE196311T1 (de) 2000-09-15
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GR3034988T3 (en) 2001-03-30
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CN1142829A (zh) 1997-02-12
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